Diabetes is a growing epidemic that is estimated to affect over 300 million people by the year 2025 pending an effective pharmaceutical cure. Type 2 diabetes accounts for 90-95% of all cases. Complications resulting from sustained elevated plasma glucose levels include cardiovascular disease, nephropathy, neuropathy, and retinopathy. Current treatments for diabetes are associated with a variety of deleterious side effects, including hypoglycemia and weight gain. In addition, current treatments for type 2 diabetes do not cure the disease but simply prolong the time until patients require insulin therapy.
Glucagon-like peptide-1 (GLP-1) is a 30 amino acid hormone secreted from gut endocrine cells in response to nutrient ingestion. GLP-1 travels through the circulation and binds to the GLP-1 receptor on the pancreas, resulting in an increase in insulin secretion. In addition, it has been shown that GLP-I reduces gastric emptying which decreases the amount of glucose that is released into the circulation. These actions combine to lower blood glucose levels. Thus, the mechanism of biological activity of GLP-1 suggests that it could be an attractive therapeutic for the treatment of type 2 diabetes. GLP-I also has the potential to treat obesity. Several studies have shown that GLP-1 administered either peripherally or intracerebroventricularly (ICV) decreases food intake in animal models. A study in humans shows that delivering GLP-1 continuously for five days in obese, diabetic patients resulted in a reduction in food intake and a reduction in body weight. However, GLP-I is not being developed as a therapeutic because of its exceptionally short half-life (T1/2˜1-2 min) (Holst, Gastroenterology 1994, 107, 1848-1855). It is rapidly degraded by dipeptidyl protease (DPP-IV), thus reducing the length of the peptide by 2 amino acids at the N-terminus and inactivating it.
Accordingly, there is a need for GLP-1 receptor modulators for the treatment of various metabolic diseases, such as diabetes, obesity, and metabolic syndrome.